We describe plans for establishment of The Alliance for Cellular Signaling - a large-scale (multidisciplinary and multi-institutional) collaborative effort to understand G protein-regulated and related cellular signaling systems, qualitatively and quantitatively. The Alliance will study signaling in two cells from the mouse: the cardiac myocyte and the B lymphocyte. Most of the experimental efforts of the Alliance will be carried out in its own laboratories (rather than those of its Participating Investigators) under the direction of two System Committees. These laboratories will conduct research on a scale that is larger than practical in individual laboratories and/or that is too specialized for most individuals. However, the experimental plan of the Alliance is designed to foster and catalyze conventionally funded research in laboratories throughout the entire signaling research community and thereby to leverage these efforts for the overall goals of the Alliance. We will also organize a large membership to assemble an informational database, whose core elements will be Molecule Pages that describe the properties and interactions of hundreds of relevant signaling molecules. Bridging Projects will be utilized for development and application of critical technologies. A Steering Committee will oversee all aspects of this effort. The experimental efforts of the Alliance will be directed at (1) identification and localization of all relevant molecules in the cells of interest, (2) documentation of the physical and functional interactions of these molecules with each other, (3) quantification of information flow through the signaling systems, and (4) representation of the entire system as a set of interacting processing modules that can be modeled mathematically. The Alliance has promulgated a Policy on Intellectual Property that has been accepted by all participants. All data from Alliance Laboratories will be placed in the public domain by dissemination on the Internet. Funding for the Alliance will be sought from a consortium of major pharmaceutical companies, in addition to this response to RFA GM-99- 007.